RATIONAL IMAGING

Suspected early dementiaThis article explores how imaging can be used to investigate a patient with suspected early dementia

Jonathan M Schott senior lecturer and honorary consultant neurologist 1, Jason D Warren readerand honorary consultant neurologist 1, Frederik Barkhof professor of neuroradiology 2, Martin NRossor professor of clinical neurology 1, Nick C Fox professor of clinical neurology 1

1Dementia Research Centre, Institute of Neurology, University College London, London WC1N 3BG, UK; 2Radiology and Image Analysis Centre(IAC), VU Medical Centre, Amsterdam, The Netherlands

This series provides an update on the best use of different imagingmethods for common or important clinical presentations. The seriesadvisers are Fergus Gleeson, consultant radiologist, Churchill Hospital,Oxford, and Kamini Patel, consultant radiologist, Homerton UniversityHospital, London. To suggest a topic for this series, please email us atpractice@bmj.com.

A 58 year old right handed woman was referred with a threeyear history of word finding difficulty and poor memory.Problems with reading, calculation, and spelling had emergedmore recently. She could find her way around and was stilldriving. She wasmore irritable and less outgoing. Her symptomswere slowly progressive with a suggestion of day to dayvariability. There was no significant past medical history andshe took no medications. There was a family history ofcardiovascular disease but not of dementia. She did not drinkalcohol to excess but had a 25 pack year smoking history. Thephysical examination was unremarkable. The mini mental stateexamination score was 25/30: she could recall all three itemsafter a delay, but lost points on orientation, naming, calculation,and for following a three stage command. Initial investigations,including full blood count, electrolytes, liver function, thyroidfunction, erythrocyte sedimentation rate, vitamin B12, folate,and a chest x ray, were normal.

What is the differential diagnosis?Aswith many patients presenting with early cognitive problems,the differential diagnosis is wide. Anxiety and depression areassociated with cognitive symptoms and they also complicateestablished dementia. Space occupying lesions includingtumours, though unlikely, require consideration.Dementiaacquired, progressive cognitive impairmentsufficient to impair activities of daily livingis more typicallyencountered in older people, but is not uncommon at youngerages.1 In an ex-smoker with a family history of cardiovasculardisease, vascular cognitive impairment, which can be associated

with focal cognitive symptoms, depression, and insidious ratherthan stepwise cognitive decline, should be considered.Alzheimers disease is the most common neurodegenerativecause of dementia. The history of memory and executive declinein the context of fluctuations makes dementia with Lewy bodiespossible, even without parkinsonism or visual hallucinations.Naming and behavioural problems are commonly seen withinthe frontotemporal lobar degeneration spectrum, which includesbehavioural variant frontotemporal dementia (previously Picksdisease), progressive non-fluent aphasia, and semantic dementia(fluent speech with loss of word meaning).Critically, distinguishing these causes from one another hasimplications for management, as acknowledged in UK nationaldementia guidelines.2 Surgery for an intracranial mass lesion ispotentially curative, as is pharmacotherapy for depression. Evenin the absence of disease modifying therapies, other dementiadisorders still require specific treatment strategies, such asmodification of vascular risk factors in vascular cognitiveimpairment, and acetylcholinesterase inhibition for Alzheimersdisease and dementia with Lewy bodies, for example. Accuratediagnosis facilitates prognosis and counselling, referral toappropriate services and voluntary organisations, applicationsfor relevant benefits, and important lifestyle, occupational, andlegal decisions, including those related to driving.

How can brain imaging help?Although a detailed clinical assessment remains the mainstayof the evaluation of a patient with early dementia, UK,European, and US guidelines recommend that all patients withcognitive impairment should undergo structural imaging as partof the diagnostic work up.3 4 5 Brain imaging is increasinglyused to help distinguish different forms of dementia from oneanother, whereas in the past it was principally undertaken toexclude treatable intracranial mass lesions, haematomata, and

Correspondence to: J M Schott j.schott@ucl.ac.uk

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2011;343:d5568 doi: 10.1136/bmj.d5568 Page 1 of 5

Practice

PRACTICE

http://www.bmj.com/permissionshttp://www.bmj.com/subscribe

Learning points

All patients with suspected dementia should have structural brain imagingStructural imaging is useful not only for excluding intracranial space occupying lesions, but also for arriving at a specificdementia subtype diagnosisThe pattern of regional brain atrophyparticularly using high resolution volumetric magnetic resonance imaging(MRI)has value in distinguishing the common neurodegenerative causes of dementiaT2 weighted and fluid attenuated inversion recovery (FLAIR) MRI sequences are highly sensitive to ischaemic damagein the cerebral white matterOther MRI sequences and imaging modalities (including positron emission tomography (PET) and dopamine transporter(DAT) scans) have diagnostic value in particular clinical settings.

hydrocephalus, which account for less than 1% of all cases ofdementia.3

Computed tomographyWhere magnetic resonance imaging (MRI) is not available orcontraindicated, computed tomography (which does involveexposure to ionising radiation) can usefully exclude major spaceoccupying lesions, hydrocephalus, and large infarcts. Modernmultidetector computed tomography scanners make it possibleto acquire volumetric imaging data of the whole brain in a fewseconds, which allows high resolution multiplanarreconstructions to be performed. Images reconstructed in thecoronal plane allow detailed assessment of the medial temporallobe structures(fig 1).

Magnetic resonance imagingMRI, with its superior contrast resolution, is increasinglypreferred over computed tomography in the evaluation ofsuspected dementia.2 A basic dementia sequence including ahigh resolution structural volumetric T1 weighted scan and T2weighted or fluid attenuated inversion recovery (FLAIR)sequences can be obtained in approximately 20 minutes. MRIdoes not involve ionising radiation, but claustrophobia may bea limiting factor in some patients. MRI is contraindicated inpatients with pacemakers and certain metallic implants, andearplugs should be worn to prevent the possibility of cochleardamage.T1 weighted volumetric MRI scanning provides a very detailedassessment of brain structure, allowing for the assessment ofthe presence or absence and pattern of brain volume loss, ie,atrophy. When evaluating a patient with cognitive impairmentit is particularly valuable to assess for medial temporal lobeatrophy on coronal reformats, either qualitatively or using simplerating scales. The presence of bilateral, symmetricalhippocampal atrophy distinguishes mild Alzheimers diseasefrom controls with approximately 80-85% sensitivity andspecificity (fig 2A).4 6 Alzheimers disease is also associatedwith relatively greater and more disproportionate hippocampalatrophy than dementia with Lewy bodies (fig 2B).7 In contrast,asymmetric temporal lobe atrophy with an anterior>posteriorgradient is at least 85% specific for frontotemporal lobardegeneration,8 and focal left inferior/anterior temporal lobeatrophy is highly suggestive of semantic dementia (fig 2C).9The presence of medial temporal lobe atrophy in patients withisolated memory impairment (mild cognitive impairment) hashigh predictive value for the subsequent development ofAlzheimers disease,10 and this has been incorporated into newproposed diagnostic criteria.11 12However, the absence of medialtemporal lobe atrophy does not exclude a diagnosis ofAlzheimers disease, and patients with young onset Alzheimers

disease may have prominent posterior atrophy with relativesparing of medial temporal lobe structures.T2 weighted or FLAIR sequences are highly sensitive fordetecting white matter abnormalities, which can reflectdemyelination but, much more commonly in this age group,cerebrovascular disease. As well as detecting major strokes,these sequences allow visualisation of small strategic infarcts(such as within the thalamus and other subcortical nuclei) andsmall vessel ischaemic white matter damage. Although anincreased white matter lesion load suggests vascular disease,particularly in combination with lesions in the basal ganglia andbrain stem, the pathophysiology and cognitive consequences ofMRIwhite matter hyperintensities remain the subject of ongoingresearch,13 and it is important not to over interpret minor vasculardisease that commonly accompanies ageing. Significant whitematter and other ischaemic changes in the presence ofhippocampal atrophy support a diagnosis of mixed vascularcognitive impairment/Alzheimers dementia (fig 2D).MRI scanning using a variety of additional sequences canprovide other valuable diagnostic information. Thus, in thecorrect clinical context, the presence of temporal lobe signalchange is suggestive of infection or inflammation (fig 3A);14diffusion weighted imaging can help distinguish acute fromchronic vascular disease, and the finding of neocortical or striatalabnormalities can aid the diagnosis of Creutzfeldt-Jakob disease(fig 3B);15 and T2* sequences sensitive to iron deposition candemonstrate microhaemorrhages due to amyloid angiopathy(fig 3C) or vascular disease.16

Metabolic and functional imagingAlthough metabolic or functional imaging is typically notperformed routinely, it can provide valuable diagnosticinformation in certain circumstances. Where dementia withLewy bodies is suspected, demonstration of central dopaminedepletion using positron emission tomography (PET) (fig 4A)or single photon emission computed tomography (SPECT)dopamine transporter (DAT) scanning has good diagnosticsensitivity and specificity (78% and 90% in one study17), andis now included as a suggestive feature in diagnostic criteria.18The demonstration of temporoparietal hypometabolism usingfluorodeoxyglucose (FDG) PET or SPECT scanning supportsa diagnosis of Alzheimers disease over frontotemporal lobardegeneration (fig 4B);19 and in patients with personality orbehavioural change in whom structural scanning is normal, thedemonstration of focal frontal hypometabolism using FDG-PETscanning supports a diagnosis of frontotemporal lobardegeneration.20Currently research tools, new PET tracers appearto have very high sensitivity and specificity for detectingcerebral amyloid pathology (Fig 4C, D), and are likely to findclinical utility in the near future.21 All these techniques involve

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2011;343:d5568 doi: 10.1136/bmj.d5568 Page 2 of 5

PRACTICE

http://www.bmj.com/permissionshttp://www.bmj.com/subscribe

the injection of radioactive tracers, with a small exposure toionising radiation.

OutcomeOur patient underwent MRI, which revealed no evidence of aspace occupying lesion, and very minor vascular load. Therewas highly asymmetric left temporal lobe atrophy with ananterior>posterior gradient (fig 2C). Neuropsychometric testingconfirmed profound anomia and semantic memory impairment.A diagnosis of frontotemporal lobar degeneration, semanticdementia variant wasmade. Treatment with acetylcholinesteraseinhibition was not indicated;2 the patient contacted the drivingauthorities and stopped driving; and was referred for speechand language therapy and to the Picks Disease Support Group.

Contributors: JMS conceived and drafted the manuscript, which wasrevised by the other authors who have all approved the final version.JDW selected the patient. JMS is the guarantor.Competing interests: All authors have completed the Unified CompetingInterest form at www.icmje.org/coi_disclosure.pdf (available on requestfrom the corresponding author) and declare: no support from anyorganisation for the submitted work; this work was undertaken atUniversity College London Hospitals/University College London, whichreceived a proportion of funding from the Department of Healths NationalInstitute for Health Research Biomedical Research Centres fundingscheme. The Dementia Research Centre is an Alzheimers ResearchUK Coordinating Centre and has also received equipment funded byAlzheimers Research UK. JMS is a UK Higher Education FundingCouncil for England clinical senior lecturer. JDW is a Wellcome Trustsenior clinical fellow. NCF is a Medical Research Council senior clinicalfellow. MNR and NCF are National Institute for Health Research seniorinvestigators. The funders did not influence the writing of this review.JMS will shortly be commencing a study with AVIDRadiopharmaceuticals Inc. who manufacture florbetapir (fig 4); theauthors report no other relationships or activities that have influencedthe submitted work.Provenance and peer review: Not commissioned; externally peerreviewed.Patient consent obtained.

1 Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementiain people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206-9.

2 National Institute for Health and Clinical Excellence (NICE). CG42 Dementia: NICEguideline. March 2011. http://guidance.nice.org.uk/CG42/NICEGuidance/pdf/English.

3 Scheltens P, Fox N, Barkhof F, De Carli C. Structural magnetic resonance imaging in thepractical assessment of dementia: beyond exclusion. Lancet Neurol 2002;1:13-21.

4 Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, et al. Practiceparameter: diagnosis of dementia (an evidence-based review). Report of the QualityStandards Subcommittee of the American Academy of Neurology. Neurology2001;56:1143-53.

5 Hort J, OBrien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, et al. EFNS guidelinesfor the diagnosis and management of Alzheimers disease. Eur J Neurol 2010;17:1236-48.

6 Duara R, Loewenstein DA, Potter E, Appel J, Greig MT, Urs R, et al. Medial temporallobe atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology2008;71:1986-92.

7 Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, et al. Medialtemporal lobe atrophy on MRI differentiates Alzheimers disease from dementia with Lewybodies and vascular cognitive impairment: a prospective study with pathological verificationof diagnosis. Brain 2009;132:195-203.

8 Likeman M, Anderson VM, Stevens JM, Waldman AD, Godbolt AK, Frost C, et al. Visualassessment of atrophy on magnetic resonance imaging in the diagnosis of pathologicallyconfirmed young-onset dementias. Arch Neurol 2005;62:1410-5.

9 Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, et al. Patterns oftemporal lobe atrophy in semantic dementia and Alzheimers disease. Ann Neurol2001;49:433-42.

10 Fox NC, Schott JM. Imaging cerebral atrophy: normal ageing to Alzheimers disease.Lancet 2004;363:392-4.

11 Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, etal. Research criteria for the diagnosis of Alzheimers disease: revising the NINCDS-ADRDAcriteria. Lancet Neurol 2007;6:734-46.

12 Albert MS, Dekosky ST, Dubois B, Feldman HH, Fox NC, Dickson D, et al. The diagnosisof mild cognitive impairment due to Alzheimers disease: recommendations from theNational Institute on AgingAlzheimers Association workgroups on diagnostic guidelinesfor Alzheimers disease. Alzheimers Dement 2011;7:270-9.

13 Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, et al. Changes inwhite matter as determinant of global functional decline in older independent outpatients:three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ2009;6;339:b2477.

14 Schott JM. Limbic encephalitis: a clinicians guide. Pract Neurol 2006;6:143-53.15 Macfarlane RG, Wroe SJ, Collinge J, Yousry TA, Jger HR. Neuroimaging findings in

human prion disease. J Neurol Neurosurg Psychiatry 2007;78:664-70.16 Cordonnier C, van der Flier WM. Brain microbleeds and Alzheimers disease: innocent

observation or key player? Brain 2011;134:335-44.17 McKeith I, OBrien J, Walker Z, Tatsch K, Booij J, Darcourt J, et al. Sensitivity and

specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia withLewy bodies: a phase III, multicentre study. Lancet Neurol 2007;6:305-13.

18 McKeith IG, Dickson DW, Lowe J, Emre M, OBrien JT, Feldman H, et al. Diagnosis andmanagement of dementia with Lewy bodies: third report of the DLB Consortium.Neurology2005;65:1863-72.

19 Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, et al. FDG-PETimproves accuracy in distinguishing frontotemporal dementia and Alzheimers disease.Brain 2007;130:2616-35.

20 Kipps CM, Hodges JR, Fryer TD, Nestor PJ. Combined magnetic resonance imaging andpositron emission tomography brain imaging in behavioural variant frontotemporaldegeneration: refining the clinical phenotype. Brain 2009;132:2566-78.

21 Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, et al. Use offlorbetapir-PET for imaging beta-amyloid pathology. JAMA 2011;305:275-83.

Cite this as: BMJ 2011;343:d5568 BMJ Publishing Group Ltd 2011

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2011;343:d5568 doi: 10.1136/bmj.d5568 Page 3 of 5

PRACTICE

http://www.icmje.org/coi_disclosure.pdfhttp://guidance.nice.org.uk/CG42/NICEGuidance/pdf/Englishhttp://www.bmj.com/permissionshttp://www.bmj.com/subscribe

Further reading

Neuroimaging in dementia. Barkhof F, Fox NC, Bastos-Leite AJ, Scheltens P, eds. Springer-Verlag, 2011

Figures

Fig 1 Bilateral medial temporal lobe atrophy (right hippocampus illustrated with arrows) in the same subject with Alzheimersdisease demonstrated on coronal images acquired with: (A) 64 detector row computed tomography scanning; (B) 1.5 teslaMRI volumetric T1 weighted sequence (adapted from Wattjes MP, Henneman WJ, van der Flier WM, de Vries O, TrberF, Geurts JJ, et al. Diagnostic imaging of patients in a memory clinic: comparison of MR imaging and 64-detector row CT.Radiology 2009;253:174-83, with permission)

Fig 2 (A) T1 weighted coronal volumetric MRI at 1.5 tesla showing symmetrical medial temporal lobe (MTL) atrophy (circled)in postmortem proven Alzheimers disease; (B) T1 weighted coronal volumetric MRI at 1.5 tesla showing relative sparingof MTL structures (circled) in postmortem proven dementia with Lewy bodies; (C) T1 weighted coronal volumetric MRI at3 tesla showing highly asymmetric inferior left temporal lobe and hippocampal atrophy (arrows) in frontotemporal lobardegeneration, semantic dementia subtype; (D) T2 weighted coronal volumetric MRI at 1.5 tesla showing symmetrical MTLatrophy (circled) and small vessel white matter disease (arrows) in a patient with clinically diagnosed mixedvascular/Alzheimers disease (D: adapted from Bastos Leite AJ, Scheltens P, Barkhof F. Pathological aging of the brain:an overview. Top Magn Reson Imaging 2004;15:369-89, with permission)

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2011;343:d5568 doi: 10.1136/bmj.d5568 Page 4 of 5

PRACTICE

http://www.bmj.com/permissionshttp://www.bmj.com/subscribe

Fig 3 (A) Axial FLAIRMRI showing left hippocampal swelling and hyperintensity (arrow) in voltage gated potassium channelcomplex antibody associated limbic encephalitis; (B) Axial diffusion weighted MRI in a patient with sporadic Creutzfeldt-Jakobdisease demonstrating widespread areas of confluent bilateral cortical restricted diffusion with similar restricted diffusionin the caudate nuclei and left putamen; (C) axial gradientecho T2* weighted imaging demonstrates multiple microbleeds(examples circled) indicating cerebral amyloid angiopathy in a patient with familial Alzheimers disease (A: adapted fromBarkhof F, Fox NC, Bastos-Leite AJ, Scheltens P, eds. Neuroimaging in dementia. Springer-Verlag, 2011, with permission;B: image courtesy Harpreet Hyare, MRC Prion Unit, University College London; C: adapted from Ryan NS, Bastos-LeiteAJ, Rohrer JD, Werring DJ, Fox NC, Rossor MN, et al. Cerebral microbleeds in familial Alzheimers disease. Brain 2011:Jun 17, with permission)

Fig 4 (A) Dopamine transporter imaging shows symmetrical reduced basal ganglia uptake (dot-like, rather than comma-like,in appearance) in a patient with clinically probable dementia with Lewy bodies; (B) FDG-PET shows right frontotemporalhypometabolism (arrow) in a patient with clinically probable behavioural variant frontotemporal dementia. Warm coloursrepresent high glucose uptake; (C, D) F18 (florbetapir) amyloid PET imaging shows absence of significant binding in (C) anormal control; and (D) significant amyloid deposition (warm/hot colours) in a patient with clinically diagnosed Alzheimersdisease (images courtesy of AVID Radiopharmaceuticals, Inc.)

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2011;343:d5568 doi: 10.1136/bmj.d5568 Page 5 of 5

PRACTICE

http://www.bmj.com/permissionshttp://www.bmj.com/subscribe